17β-acyl-4-aza-5α-androst-1-ene-3-ones as 5α-reductase inhibitors

ABSTRACT

17β-Acyl-4-aza-5α-androst-1-ene-3-ones of the formula ##STR1## wherein R is selected from hydrogen, methyl and ethyl and 
     R 2  is monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or more halo (Cl or Br) substituents; 
     and R&#39;, R&#34; and R&#39;&#34; are each selected from hydrogen and methyl and pharmaceutical formulation of the above compounds are active as testosterone 5α-reductase inhibitors and thus are useful for treatment of acne, seborrhea, female hirsutism, androgenic alopecia, prostatic carcinoma and benign prostatic hypertrophy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. Ser. No. 363,567, filed June 8,1989, pending, which in turn is a continuation of U.S. Ser. No. 129,335,filed Dec. 3, 1987, now U.S. Pat. No. 4,859,681 which in turn is acontinuation of U.S. Ser. No. 800,624, filed Nov. 21, 1985, nowabandoned, which in turn is a continuation of U.S. Ser. No. 584,061,filed Feb. 27, 1984, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is concerned with novel17β-acyl-4-aza-5α-androst-1-ene-3-one compounds and the use of suchcompounds as testosterone-5α-reductase inhibitors.

DESCRIPTION OF THE PRIOR ART

It is well known in the art that certain undesirable physiologicalmanifestations, such as acne vulgaris, seborrhea, female hirsutism, andmale pattern baldness and benign prostatic hypertrophy, are the resultof hyperandrogenic stimulation caused by an excessive accumulation oftestosterone or similar androgenic hormones in the metabolic system.Early attempts to provide a chemotherapeutic agent to counter theundesirable results of hyperandrogenicity resulted in the discovery ofseveral steroidal antiandrogens having undesirable hormonal activitiesof their own. The estrogens, for example, not only counteract the effectof the androgens but have a feminizing effect as well. Non-steroidalantiandrogens have also been developed, for example,4'-nitro-3'-trifluoromethylisobutyranilide. See Neri et al., Endo., Vol.91, No 12 (1972). However, these products, though devoid of hormonaleffects, are peripherally active, competing with the natural androgensfor receptor sites, and hence have a tendency to feminize a male host orthe male fetus of a female host.

It more recently became known in the art that the principal mediator ofandrogenic activity in some target organs is 5α-dihydrotestosterone, andthat it is formed locally in the target organ by the action oftestosterone-5α-reductase. It therefore has been postulated anddemonstrated that inhibitors of testosterone-5α-reductase will serve toprevent or lessen symptoms of hyperandrogenic stimulation. Nayfeh etal., Steroids, 14, 269 (1969) demonstrated in vitro that methyl4-androsten-3-one-17β-carboxylate was a testosterone-5α-reductaseinhibitor. Then Voigt and Hsia, Endocrinology, 92, 1216 (1973), CanadianPat. No. 970,692, demonstrated that the above ester and the parent freeacid, 4-androsten-3-one-17β-carboxylic acid are both active inhibitorsof testosterone-5α-reductase in vitro. They further demonstrated thattopical application of either testosterone or 5α-dihydrotestosteronecaused enlargement of the female hamster flank organ, or androgendependent sebaceous structure. However, concomitant administration of4-androsten-3-one-17β-carboxylic acid or its methyl ester inhibited theresponse elicited by testosterone but did not inhibit the responseelicited by 5α-dihydrotestosterone. These results were interpreted asindicating that the compounds were antiandrogenic by virtue of theirability to inhibit testosterone-5α-reductase.

A number of 4-aza steroid compounds are known. See, for example, U.S.Pat. Nos. 2,227,876; 3,239,417; 3,264,301; and 3,285,918; French Pat.No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640(1973); Doorenbos and Brown, J. Pharm. Sci., 60, 8, pp. 1234-1235(1971); and Doorenbos and Kim, J. Pharm. Sci., 63, 4, pp. 620-622(1974).

In addition U.S. Pat. Nos. 4,377,584 and 4,220,775 of Rasmusson et al.describe a group of 4-aza-5α-17β-substituted-5α-androsten-3-ones whichare said to be useful in the treatment of hyperandrogenic conditions.However, none of the cited references suggest that any of the novel17β-acyl-4-aza-5α-androst-1-ene-3-ones of the present invention wouldhave utility as highly potent testosterone-5α-reductase inhibitors.

DESCRIPTION OF THE INVENTION

The present invention is concerned with novel17β-acyl-4-aza-5α-androst-1-ene-3-one compounds, processes for theirpreparation, pharmaceutical formulations comprising the novel compoundsas active ingredients and methods of inhibitingtestosterone-5α-reductase and of treating hyperandrogenic conditionswith the novel compounds or their pharmaceutical formulations.

The present invention is concerned with17β-acyl-4-aza-5α-androst-1-ene-3-one compounds of the formula: ##STR2##wherein R is selected from hydrogen, methyl and ethyl; and

R² is a monovalent radical selected from straight and branched chainalkyl of from 1-12 carbons, or monocyclic aryl optionally containing 1or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 ormore halo (Cl or Br) substituents, aralkyl selected from benzyl andphenethyl and heterocyclic selected from 2- or 4-pyridyl, 2-pyrrolyl,2-furyl or thiophenyl and R', R" and R'" are each selected from hydrogenand methyl.

A preferred embodiment of the novel compounds of our invention isrepresented by the formula: ##STR3## wherein R is hydrogen, methyl orethyl, and

R³ is branched chain alkyl, or cycloalkyl of from 4-8 carbons.

An especially preferred embodiment of the invention is the compounds offormula II where R³ is phenyl, phenyl substituted by 1 or 2 lower alkylsubstituents of from 1 to 2 carbon atoms, and phenyl substituted by 1 or2 halo (Cl, F or Br) substituents.

Representative compounds of the present invention include the following:

17β-(t-butylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(isobutylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(isooctylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(n-octylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(1,1-diethylbutylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(neopentylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(tert-amylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(tert-hexylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(5-butylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

and the corresponding compounds wherein the 4-methyl substituent isreplaced in each of the above named compounds by a hydrogen or an ethylradical.

Also included as representative compounds are any of the above indicatedcompounds having the alkyl of the alkyl carbonyl substituent replaced bya methyl-, ethyl-, propyl-, i-propyl-, butyl-, phenyl-, 2-, 3- or4-tolyl-, xylyl-, 2-bromo-or 2-chlorophenyl-, 2,6-dichloro- or a2,6-dibromophenyl carbonyl substituent or a heterocyclic substituentselected from 2 or 4-pyridyl, 2-pyrrolyl, 2-furyl or 2-thiophenyl.

These representative compounds are:

17β-(phenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(3-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(4-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2-bromophenylcarbonyl)-4-aza-4-methyl-5α-1-ene-androst-3-one;

17β-(2-chlorophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2,6-dichlorophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(2,6-dibromophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(xylylphenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;

17β-(phenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(3-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(4-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-bromophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2-chlorophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2,6-dichlorophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(2,6-dibromophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;

17β-(xylylcarbonyl)-4-aza-5α-androst-1-ene-3-one.

The novel compounds of formula I or II of the present invention areprepared by a method starting with the known steroid ester of theformula: ##STR4## which includes the stages of (1) dehydrogenating saidstarting material to produce the corresponding compound containing adouble bond in the 1,2-position of the A-ring, (2) converting the17-carbomethoxy substituent into a 17β-acyl substituent and, if desired(3) alkylating the A-ring nitrogen to introduce 4-methyl or 4-ethylsubstituents into the A-ring. In carrying out the process of the presentinvention, it is essential that stage (1) dehydrogenation of the1,2-position of the steroid A-ring be carried out using a4-aza-5α-androsten-3-one compound having no substituent other thanhydrogen attached to the A-ring nitrogen. Stage (2) may consist of oneor more chemical steps and if desired may take place before stage (1) orfollowing stage (1) or stage (3).

In accordance with the process of the present invention, the products ofour invention are formed by (1) heating a17β-alkoxycarbonyl-4-aza-5α-androstan-3-one compound III with adehydrogenating agent such as benzeneseleninic anhydride in refluxingchlorobenzene to form a 17β-alkoxycarbonyl-4-aza-5α-androst-1-en-3-one(IV), (2) the formed 5α-androst-1-en-3-one compound from step (1) isreacted with sodium hydride and under anhydrous conditions in a neutralsolvent such as dimethylformamide, (2) contacting the resulting reactionmixture with an alkyl (methyl or ethyl) iodide to form the corresponding17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst-1-en-3-one (V), (3)subsequently hydrolyzing said17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst-1-en-3-one with a strongbase such as aqueous methanolic potassium hydroxide at the refluxtemperature, followed by acidification and isolation of the resultingsteroidal acid, 17β-carboxy-4-alkyl-4-aza-5α-androst-1-en-3-one (VI),(4) said steroidal acid is then converted to its corresponding2-thiopyridyl ester by refluxing with triphenyl phosphine and2,2'-dipyridyl disulfide in an inert solvent and the product17β-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one (VII) isisolated by chromatography on silica, (5) said pyridylthio ester is thenreacted with an R² -Li or an R² MgX (X=Cl, Br) compound such assec-butylmagnesium chloride in tetrahydrofuran to form the desiredproduct 17β-(sec-butylcarbonyl)-4-alkyl-4-aza-5α-androst-1-en-3-one(VIII) which is isolated by chromatography on silica gel. When theprevious reaction is carried out using an R² MgX or, an R² -Li compoundin place of sec-butylmagnesium chloride, the corresponding17β-(acyl)-4-alkyl-4-aza-5α-androst-1-en-3-one is prepared wherein acylis R² carbonyl.

In accordance with the process of our invention, the corresponding17β-acyl-4-aza-5α-androst-1-en-3-one XV is readily prepared from the17β(alkoxycarbonyl)-4-aza-5α-androsten-3-one (IV) by repeating the aboveseries of reaction steps but omitting step 2 hereinabove, i.e.,treatment of the 4-aza-5α-androst-1-en-3-one with sodium amide followedby methyl or ethyl iodide.

In accordance with a further alternate process of preparing thecompounds of our invention, having only hydrogen as the sole substituenton the ring A-nitrogen, the Ω' double bond in the A-ring is introducedas the last step of the process. Thus, a17β-alkoxycarbonyl-4-aza-5α-androstan-3-one (III) is hydrolyzed to thecorresponding steroidal acid, 17β-carboxy-4-aza-5α-androstan-3-one, (IX)which, in turn, is converted to the corresponding thiopyridyl ester,17β-(2-pyridylthiocarbonyl)-4-aza-5α-androstan-1-one (X) followed bytreatment of the ester with an R² MgX or R² Li compound wherein R² is asdefined hereinabove to form a 17β-(acyl)-4-aza-5α-androstan-3-one (XI)which is dehydrogenated as previously described to produce compound XIV,17β-(acyl)-4-aza-5α-androst-1-en-3-one.

In an additional alternative process for making the compounds of formulaI and II, when the starting material is an ester, particularly methylester as shown in formula III-V in the schematic, reaction with aGrignard reagent gives the ketone corresponding to the moiety associatedwith the Grignard reagent.

The 16 methyl derivative wherein R'" is methyl are prepared from known16-methyl-17-acyl-4-methyl-4-aza-5α-androstan-3-ones, e.g.4,16β-dimethyl-17β-acetyl-4-aza-5α-androstan-3-one by knowndehydrogenation procedures for 4-methyl-4-aza compounds to produce thecorresponding 4,16β-dimethyl-17β-acetyl-4-aza-5α-androst-1-en-3-one.

The above reactions are schematically represented in the followingstructural outline: ##STR5## wherein X is a 2-pyridylthio substituentand R² is defined as hereinabove.

The compounds of the present invention, prepared in accordance with themethod described above, are, as already described, potent anti-androgensby virtue of their ability to specifically inhibittestosterone-5α-reductase.

Accordingly, the present invention is particularly concerned withproviding a method of treating the hyperandrogenic conditions of acnevulgaris, seborrhea, and female hirsutism by topical administration, anda method of treating all of the above conditions as well as benignprostatic hypertrophy, by parenteral administration, of the novelcompounds of the present invention.

The present invention is thus also concerned with providing suitabletopical and parenteral pharmaceutical formulations for use in the novelmethods of treatment of the present invention.

The compositions containing the compounds of the present invention asthe active ingredient for use in the treatment of benign prostatichypertrophy can be administered in a wide variety of therapeutic dosageforms in conventional vehicles for systemic administration, as, forexample, by oral administration in the form of tablets, capsules,solutions, or suspensions, of by intravenous injection. The daily dosageof the products may be varied over a wide range varying from 50 to 2,000mg. The compositions are preferably provided in the form of scoredtablets containing 5, 10, 25, 50, 100, 150, 250, and 500 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.005 mg to about 50 mg/kg ofbody weight per day. Preferably the range is from about 0.01 mg to 5mg/kg of body weight per day. These dosages are well below the toxicdose of the product. Capsules containing the product of this inventioncan be prepared by mixing an active compound of the present inventionwith lactose and magnesium stearate, calcium stearate, starch, talc, orother carriers, and placing the mixture in gelatin capsule. Tablets maybe prepared by mixing the active ingredient with conventional tabletingingredients such as calcium phosphate, lactose, corn starch or magnesiumstearate. The liquid forms in suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methylcellulose and the like. Other dispersing agents which maybe employed include glycerin and the like. For parenteral administrationsterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservative are employed whenintravenous administration is desired.

For the treatment of acne vulgaris, seborrhea, female hirsutism, thecompounds of the present invention are administered in the formula ofpharmaceutical composition comprising the active compound in combinationwith a pharmacologically acceptable carrier adapted for topicaladministration. These topical pharmaceutical compositions may be in theform of a cream, ointment, gel or aerosol formulation adapted forapplication to the skin. These topical pharmaceutical compositionscontaining the compounds of the present invention ordinarily includeabout 0.1% to 15%, preferably about 5%, of the active compound, inadmixture with about 95% of vehicle.

The method of preparing the novel compounds of the present invention,already described above in general terms, may be further illustrated bythe following examples.

EXAMPLE 1 22-Methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione ##STR6##

To a solution of 7.2 g ofS-(2-pyridyl)-3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate in 288 mlof tetrahydrofuran was added at -78° C. 33.6 ml of 1.3M S-butylmagnesiumchloride. After 30 minutes at -78° C. the solution came to roomtemperature and was treated with saturated aqueous NaCl solution. Theproduct was extracted into dichloromethane and was washed with saturatedaqueous NaCl solution and 10% aqueous NaOH solution, then dried andconcentrated. The residue was eluted through 430 g of silica gel with9:1 dichloromethane-acetone to give 4.5 g of the product, m.p. 246°-249°C.

When the procedure is repeated using the following reagents, theindicated product is obtained.

    ______________________________________                                        Starting                                                                      Material     Reagent      Product                                             ______________________________________                                        S-(2-pyridyl)3-                                                                            2-pyrrolyl mag-                                                                            17β-(2-pyrrolyl-                               oxo-4-aza-5α-                                                                        nesium chloride                                                                            carbonyl)-4-aza-                                    androst-1-ene-            5α-androst-1-ene-                             17β-thiocarboxylate  3-one                                                                         m.p. 294-296° C.                             S-(2-pyridyl)3-                                                                            sec-butyl mag-                                                                             4,22-dimethyl-4-                                    oxo-4-methyl-5α-                                                                     nesium chloride                                                                            aza-21-nor-5α-                                androst-1-ene-17β-   chol-1-ene-3,20-dione                               thiocarboxylate           m.p. 134-136° C.                             S-(2-pyridyl)3-                                                                            2-pyrrolyl mag-                                                                            4-methyl-17β-(2-                               oxo-4-methyl-4-                                                                            nesium chloride                                                                            pyrrolylcarbonyl)-                                  aza-5α-androst-     4-aza-5α-androst-                             1-ene-17β-thio-      1-ene-3-one                                         carboxylate               m.p. 234-238° C.                             S-(2-pyridyl)3-                                                                            isobutyl mag-                                                                              23-methyl-4-aza-                                    oxo-4-aza-5α-                                                                        nesium chloride                                                                            2l-nor-5α-                                    androst-ene-17β-     cholane-3,20-                                       thiocarboxylate           dione                                                                         m.p. 220-222° C.                             ______________________________________                                    

EXAMPLE 2 22-Methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione ##STR7##

A solution of 21 g of 22-methyl-4-aza-21-nor-5α-cholane-3,20-dione(Step 1) and 29.49 g of benzeneseleninic anhydride in 552 ml ofchlorobenzene was refluxed with water separation for 4 hours. Themixture was concentrated and the residue was redissolved indichloromethane. After washing with 10% aqueous sodium hydroxide, then10% hydrochloric acid and saturated aqueous sodium chloride the solutionwas dried and concentrated to 45 g of yellow residue. This waschromatographed on 1.5 kg of silica gel packed in dichloromethane andeluted with ethyl acetate to give 10.6 g of the product, m.p. 248°-251°C.

When the procedure is repeated using23-methyl-4-aza-21-nor-5α-cholane-3,20-dione as starting material theproduct obtained is 23-methyl-4-aza-21-nor-5α-chol-1-ene-3,20-dione,m.p. 283°-286° C.

EXAMPLE 3 17β-(phenylcarbonyl)-4-aza-5α-androst-1-ene-3-one

To a stirred suspension of 43 g ofS-(2-pyridyl)-3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-thiocarboxylatein 500 ml of anhydrous tetrahydrofuran (THF) was added at -78° C. a THFsolution of 157 ml of 2N phenylmagnesium chloride over 60 minutes. Afterstirring at -78° C. for 60 minutes, the mixture was brought to -30° C.and was quenched by addition of 10% HCl while maintaining thetemperature below -20° C. After warming to 0° C., the mixture wasdiluted with 2000 ml of water and extracted with 4000 ml ofdichloromethane in portions. The organic layer was washed sequentiallywith water, 1N sodium hydroxide, water and saturated sodium chloridesolution. Drying with MgSO₄ and concentration afforded 37.5 g of crudeproduct. Recrystallization from dichloromethane/ethyl acetate gave thetitle phenyl ketone (30.4 g, 77% yield). m.p. 290°-291° C.

    ______________________________________                                                     Calc Found                                                       ______________________________________                                        N              3.61   3.56                                                    C              77.48  77.16                                                   H              8.26   8.19                                                    ______________________________________                                    

EXAMPLE 417-beta-4-fluorophenycarbonyl-4-aza-5-alpha-androst-1-ene-3-one

The procedure of Example 3 was repeated with suitable reagents and thetitle compound was obtained. m.p. 315°-315.5° C.

What is claimed is:
 1. A compound of formula: ##STR8## wherein R isselected from hydrogen, methyl and ethyl; andR² is monocyclic aryloptionally containing 1 or more lower alkyl substituents of from 1-2carbon atoms and/or 1 or more halo (Cl, F or Br) substituents; andR',R", R'" are each selected from hydrogen and methyl.
 2. A compound ofclaim 1 having the formula ##STR9## wherein R is hydrogen, methyl orethyl; andR³ is phenyl, phenyl substituted by 1 or 2 lower alkylsubstituents of from 1 to 2 carbon atoms, phenyl substituted by 1 or 2halo (Cl, F or Br) substituents.
 3. A compound of claim 2 whereinR³ isphenyl, 2-, 3-, or 4-tolyl, xylyl, 2-bromo or 2-chlorophenyl,2,6-dichloro or 2,6-dibromophenyl.
 4. A compound of claim 3 whichis17β-(phenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;17β-(2-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;17β-(3-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;17β-(4-tolylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;17β-(2-bromophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;17β-(2-chlorophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;17β-(2,6-dichlorophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;17β-(2,6-dibromophenylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one;17β-(xylylcarbonyl)-4-aza-4-methyl-5α-androst-1-ene-3-one.
 5. A compoundaccording to claim 3 whichis17β-(phenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;17β-(2-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;17β-(3-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;17β-(4-tolylcarbonyl)-4-aza-5α-androst-1-ene-3-one;17β-(2-bromophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;17β-(2-chlorophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;17β-(2,6-dichlorophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one;17β-(2,6-dibromophenylcarbonyl)-4-aza-5α-androst-1-ene-3-one.
 6. Acompound of claim 5 which is17β-(phenylcarbonyl)4-aza-5α-androst-1-ene-3-one.
 7. A method oftreating the hyperandrogenic condition of acne vulgaris, seborrhea,female hirsutism, and benign prostatic hypertrophy comprisingadministrating to a patient in need of such treatment of atherapeutically effective amount of a compound of claim
 1. 8. A methodof inhibiting testosterone 5α-reductase in a patient in need of suchinhibiting treatment comprising administration to such a patient of atherapeutically effective amount of a compound of the claim
 1. 9. Apharmaceutical composition for inhibiting testosterone 5α-reductasewhich comprises a pharmaceutically acceptable carrier and an effectiveamount of a compound of claim 1.